It is our overall aim to determine the mechanisms responsible for mediation of long-term ventilatory adaptation. To this end, three areas of research will each be devoted to a specific problem: 1. What is the relative contribution of brain (H ion) to eupnea in the presence of varying ventilatory stimuli or inhibition? This will be determined through use of the ventricular:cisternal perfuson technique in awake goats (and rats) whereby both the ionic composition of brain interstitial fluid and the changing sensitivity of medullary chemoreceptors is determined. 2. What are the influences of physiologic sleep - as a model of predominant "metabolic" control of ventilation - on ventilatory adaptation to chronic stimuli and depressants in health and in the human control system already compromised by chronic lung disease? The interaction of sleep with chronic metabolic alkalosis and acidosis, hypoxia and progesterone will be studied. In patients with COPD and chronic CO2 retention the effects of acidification and progesterone therapy on sleep ventilation will be contrasted with the aim of determining mechanisms of chronic CO2 retention and its correction. 3. How and through what site(s) of action does monoamine metabolism effect ventilatory control? Rats, cats and goats will be used to determine the effect and site of effect of pharmacologic blockade and physiologic depletion of serotonin and norepinephrine on ventilatory control and adaptation.